WO2000008005A2

WO2000008005A2 - Piperazinone derivatives

Info

Publication number: WO2000008005A2
Application number: PCT/EP1999/005070
Authority: WO
Inventors: Dieter Dorsch; Horst Juraszyk; Werner Mederski; Hanns Wurziger; Hans-Peter Buchstaller; Sabine Bernotat-Danielowski; Guido Melzer; Joachim Gante
Original assignee: Merck Patent Gmbh; GANTE, Helga
Priority date: 1998-08-08
Filing date: 1999-07-16
Publication date: 2000-02-17
Also published as: AU5411499A; AR020124A1; WO2000008005A3; DE19835950A1

Abstract

The present invention relates to new piperazinone derivatives of the formula (I), in which R?1, R2, R3, R4, R5, R6, R7, R8¿, W and X are such as defined in claim 1, as well as to the salts and solvates thereof. These derivatives are inhibitors of the coagulation factor Xa and can be used for preventing and/or treating thromboembolic disorders.

Description

Piperazinone derivatives

The invention relates to piperazinone derivatives of the formula I.

wherein

R ¹ , R ² independently of one another A, unsubstituted or mono-, di- or triple by R ⁸ , A, Ar ', OH, OA, O (C (R ³ ) ₂ ) _n -Ar, OAr', NH ₂ , NHA, NA ₂ , NO ₂ , CN, shark, NHCOA, NHCOAr ', NHSO ₂ A, NHSO ₂ Ar', COOH, COOA, CONH ₂ , CONHA, CONA ₂ , CONHAr ', COA, COAr', S (O) _n A, S (O) _π Ar \ SO ₂ NH ₂ , SO ₂ NHA or SO ₂ NA ₂ substituted phenyl, naphthyl or biphenyl or a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N-, O- and / or S atoms, bonded via N or C, which is unsubstituted or mono- or triple by R ⁸ , A, Ar ', OH, OA, O (C (R ³ ) ₂ ) _n - Ar, OAr' , NH ₂ , NHA, NA ₂ , NO ₂ , CN, shark, NHCOA, NHCOAr ', NHSO ₂ A, NHSO ₂ Ar', COOH, COOA, CONH ₂ , CONHA, CONA ₂ ,

CONHAr ', COA, COAr', S (O) _n A, S (O) _n Ar '. SO ₂ NH ₂ , SO ₂ NHA or SO ₂ NA ₂ or carbonyl oxygen can be substituted, with the proviso that the radical R ⁸ must be present at least once in R or in R ² or in both radicals R ¹ and R ² each can happen once

R ³ H or A,

R ⁴ , R ⁵ ,

R ⁶ , R ⁷ each independently of one another H, A, (C (R ³ ) ₂ ) _n -Ar, (C (R ³ ) ₂ ) _n -Het, (C (R ³ ) ₂ ) _n -COOR ³ , R ^{8 is} unsubstituted or simply by COA, CO- [C (R ³ ) ₂ ] _π -Ar,

COOA, OH or C (= NH) -NH ₂ substituted by a conventional amino protecting group, unsubstituted NH-C (= NH) -NH ₂ , CON = C (NH ₂ ) ₂ ,

W -CO-, -C (R ³ ) ₂ ,

X - (C (R ³ ) ₂ ) _π . -S0 _2l -CO-, -COO-, -CONR ⁴ -,

A alkyl with 1-20 carbon atoms, in which one or two CH ₂ groups pass through

O or S atoms or by -CR ³ = CR ³ groups and also 1-7 H-

Atoms can be replaced by F, Ar unsubstituted or one, two or three times by A, Ar ', OH, OA,

OAr ', O (C (R ³ ) ₂ ) _n -Ar, NH ₂ , NHA, NA ₂ , NO ₂ , CN, shark, NHCOA,

NHCOAr ', NHSO ₂ A, NHSO ₂ Ar', COOH, COOA, CONH ₂ , CONHA,

CONA ₂ , CONHAr ^* , COA, COAr ', S (O) _n A or 5 (0) ^' substituted phenyl or naphthyl, Ar 'unsubstituted or one, two or three times by A, OH, OA,

NH ₂ , NHA, NA ₂ , NO ₂ , CN, shark, NHCOA, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , COA or S (θ \ substituted phenyl or

Naphthyl, Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, bound via N or C, which is unsubstituted or mono-, di- or triple by shark, A. , Ar ', OH, OA, O (C (R ³ ) ₂ ) _n -Ar', COOH, COOA,

CN, NO ₂ , NH ₂ , NHA, NA ₂ , NHCOA, NHCOAr 'or

Carbonyl oxygen can be substituted, Hai F, Cl, Br or I, n 0, 1 or 2, and their pharmaceutically acceptable salts and solvates. The invention also relates to the optically active forms, the racemates and the diastereomers of these compounds.

The invention was based on the task of finding new compounds with valuable properties, in particular those which

Manufacture of drugs can be used.

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. In particular, they show factor Xa inhibitory properties and can therefore be used to combat and prevent thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermittently.

The compounds of the formula I according to the invention can furthermore be inhibitors of the coagulation factors factor VIIa, factor IXa and thrombin of the blood coagulation cascade.

Aromatic amidine derivatives with antithrombotic activity are e.g. known from EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic disorders are e.g. described in WO 97/08165. Aromatic heterocycles with factor Xa inhibitory activity are e.g. known from WO 96/10022. Substituted N- [(aminoiminomethyl) phenylalkyl] azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.

The antithrombotic and anticoagulant effect of the compounds according to the invention is known as the inhibitory effect against the activated gene protease Factor Xa, or attributed to the inhibition of other activated optic proteases such as factor VIII, factor IXa or thrombin.

Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of

Prothrombin in thrombin. Thrombin cleaves fibrinogen into fibrin monomers, which after cross-linking make an elementary contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders. However, inhibition of thrombin can inhibit fibrin formation involved in thrombus formation.

The measurement of the inhibition of thrombin can e.g. using the method of G.F. Cousins et al. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa can thus prevent thrombin from being formed.

The compounds of formula I according to the invention and their salts interfere with the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.

The inhibition of factor Xa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is e.g. by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.

The measurement of the inhibition of factor Xa can, for example, by the method of T. Hara et al. in thromb. Haemostas. 1994, 71, 314-319. The coagulation factor VIa initiates the extrinsic part of the coagulation cascade after binding to the tissue factor and contributes to the activation of the factor X to factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and thus the subsequent formation of thrombin.

The inhibition of the Vlla factor by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A common method for measuring the inhibition of factor VIIa is e.g. by H. F. Ronning et al. in

Thrombosis Research 1996, 84, 73-81.

Coagulation factor IXa is generated in the internal coagulation cascade and is also involved in the activation of factor X to factor Xa. Inhibition of factor IXa can therefore otherwise prevent factor Xa from being formed. The inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Chang et al. in Journal of Biological Chem / ^' s ty 1998, 273, 12089-12094.

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for

Combating and preventing thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication. The invention relates to the compounds of the formula I and their salts and solvates and to a process for the preparation of compounds of the formula I as claimed in claim 1 and their salts and solvates, characterized in that a) they are obtained from one of their functional derivatives by treatment with a liberates solvolysing or hydrogenolysing agents by i) releasing an amidino group from its oxadiazole derivative by hydrogenolysis,

ii) replacing a conventional amino protecting group with hydrogen by treatment with a solvolysing or hydrogenolysing agent or releasing an amino group protected by a conventional protecting group, or b) for the preparation of compounds of the formula I,

living R ⁸ means

and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , W and X have the meanings given in Claim 1,

a compound of formula II

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and W have the meanings given in claim 1 and

R ⁸ means

with a compound of formula III

R ² -XL III wherein

R ² and X have the meanings given in Claim 1 and L is Cl, Br, I or a free or reactive functional OH group, or c) in a compound of the formula I one or more radicals W, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and / or R ⁸ into one or more radicals W, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and / or R ⁸ converts, for example by

i) converting a cyano group to an amidino group, ii) hydrolyzing an ester group to a carboxy group, iii) esterifying a carboxy group, iv) reducing a nitro group, v) acylating an amino group, vi) alkylating a sulfonylamino group or alkylating it

Dealkylated sulfonylamino group, and / or d) converting a base or acid of the formula I into one of its salts or solvates. Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are, for example, mono- or dihydrates or alcoholates.

For all radicals that occur more than once, such as R ⁸ , the meanings are independent of one another.

Above and below, the radicals or parameters X, W, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and n have those given in the formulas I to III

Meanings, unless expressly stated otherwise.

In the above formulas, A is alkyl, is linear or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. A is preferably methyl, furthermore ethyl, propyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3, 3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl.

A also means e.g. Tifluoromethyl, pentafluoroethyl, allyl or crotyl.

Ar preferably denotes unsubstituted phenyl or naphthyl, further preferably by A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, phenyloxy, benzyloxy,

Phenethyloxy, naphthyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamonamyl, methylsulfonylamino, butylsulfonamamyl, methylsulfonylamino, methylsulfonylamino, methylsulfonylamino, methylsulfonylamino, Phenylsulfonamido, (4-methylphenyl) sulfonamido, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, phenylaminocarbonyl, acyl or benzoyl or also mono-, di- or di-mono-, di- or di-mono, di- or di-substituted or

Biphenyl, where A has the meanings given above.

Ar therefore preferably means o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propyiphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or pN, N-dimethylaminophenyl, o-, m- or p-sulfonamidophenyl, o-, m- or p-nitrophenyl, o -, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-, p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o -, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m-, p-carboxyphenyl, o-, m-, p-methoxycarbonylphenyl, o-, m-, p-acetylphenyl, o -, m-, p-formylphenyl, o-, m-, p-methylsulfonylphenyl, o-, m-, p-phenylsulfonamidophenyl, o-, m-, p-methylsulfonamidophenyl or, o-, m-, p-methylthiophenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2, 6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or

3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4-, 2,5 -, 2,6-, 3,4- or 3,5-dimethoxyphenyl.

Ar 'preferably denotes unsubstituted phenyl or naphthyl, further preferably by A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, methylthio, ethylthio, methylsulfinyi, ethylsulfmyl, methylsulfonyl, ethylsulfonyl, nitro, Amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, carboxymethoxy, carboxyethoxy, Methoxycarbonylmethoxy, methoxycarbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, acyl or benzoyl mono-, di- or tri-substituted phenyl or naphthyl, where A has the meanings given above.

Ar 'therefore preferably means o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or pN, N-dimethylaminophenyl, o-, m- or p-sulfonamidophenyl, o-, m- or p-nitrophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-, p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m-, p-carboxyphenyl, o-, m-, p-methoxycarbonylphenyl, o-, m-, p-acetylphenyl, o-, m-, p-formyiphenyl, o-, m-, p-methylsulfonylphenyl, o-, m-, p-methylsulfonamidophenyi or, o-, m-, p-methylthiophenyl, more preferably 2,3-, 2, 4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3rd , 5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5- , 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2, 3- , 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl.

Shark is preferably F, Cl or bromine.

Het is preferably unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,

4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, -4 or -5-yl , 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl 1, 2,4-oxadiazol-3- or -5-yl, 1, 3,4-thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4 -Pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3 -, 4-, 5-, 6- or 7-1 H-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-,

4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5- , 6- or 7-benz-2,1, 3-oxadiazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6- Quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl , 2,1, 3-benzothiadiazol-4- or -5-yl or 2,1, 3-benzoxadiazol-5-yl. The heterocyclic radicals can also be partially or completely hydrogenated. Het can also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro -2- or -3-furyl, 1, 3- dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrroidinyl, tetrahydro-1-, -2- or -3-pyrollyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6-, -7- 1 H-indoiyl, 2,3-dihydro- 1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4-dihydro -1-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, - 5- or -6-pyridyl , 1, 2,3,6-tetrahydro-1-, -2-, -3, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, 2-, 3- or

4-morpholinyl, tetra hydro-2-, -3- or -4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxan- 2-, -4- or -5-yl, hexahydro-1-, -3 - or -4-pyridazinyl, hexahydro-1-, -2-, - 4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3,4-tetrahydro-1-, -2 -, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4 -, -5-, -6-, -7- or -8-isoquinolinyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H- benzo [1, 4] oxazinyl, more preferably 2, 3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydro-benzofuran -5- or -6-yl, 2,3- (2-oxo-methylenedioxy) phenyl or 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, further 2,3 -Dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het is unsubstituted or one, two or three times by shark, A, Ar ', COOH, COOA, OH, OA, O (C (R ³ ) ₂ ) _n -Ar', CN, NO ₂ , NH ₂ , NHA , NA ₂ , NHCOA, NHCOAr 'or carbonyl oxygen, where shark, A and Ar' have one of the meanings given above and R ^{3 has} one of the meanings given below.

Irrespective of R ^2, R ¹ preferably denotes A, unsubstituted or mono-, di- or triple by R ⁸ , A, Ar ', OH, OA, O (C (R ³ ) ₂ ) _n -Ar, OAr', NH ₂ ,

NHA, NA ₂ , NO ₂ , CN, shark, NHCOA, NHCOAr ', NHSO ₂ A, NHSO ₂ Ar', COOH, COOA, CONH ₂ , CONHA, CONA ₂ , CONHAr ', COA, COAr ^* , S (O) _n A, 3 (0) ^ ', SO ₂ NH ₂ , SO ₂ NHA or SO ₂ NA ₂ substituted phenyl, naphthyl or biphenyl or a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N-, O- and / or S atoms, bonded via N or C, which is unsubstituted or mono- or triple by R ⁸ , A, Ar ', OH, OA, O (C (R ³ ) ₂ ) _n -Ar, OAr' , NH ₂ , NHA, NA ₂ , NO ₂ , CN, shark, NHCOA, NHCOAr ', NHSO ₂ A, NHSO ₂ Ar', COOH, COOA, CONH ₂ , CONHA, CONA ₂ , CONHAr ¹ , COA, COAr ', S (O) Λ S ^^ r ', SO ₂ NH ₂ , SO ₂ NHA or SO ₂ NA ₂ or carbonyl oxygen can be substituted, where A, Ar' and Hai have one of the meanings given above and R ³ and R ^{8 have} one have the meanings given below. The meaning of the mono- or dinuclear saturated, unsaturated or aromatic heterocycle is in accordance with the meaning of Het given above. Particularly preferred for R ¹ is unsubstituted phenyl, 2-naphthyl, 3-naphthyl or 4-biphenylyl, 2,3-, 2,4-, 2,5-, 3,4- or 3,5-dimethoxyphenyl or C ( = NH) -NH ₂ substituted phenyl, 2-naphthyl, 3-naphthyl, 3- or 4-biphenylyl.

Unsubstituted phenyl, 2-naphthyl or 4-biphenylyl, 3,5-dimethoxyphenyl, 3-amidinophenyl, 4-amidinophenyl, 7-amidino-2-naphthyl or 3'-amidino-biphenyl-3-yl is very particularly preferred for R ¹ .

Independently of R ^1, R ² preferably denotes A, unsubstituted or mono-, di- or triple by R ⁸ , A, Ar ', OH, OA, 0 (C (R ³ ) ₂ ) _n -Ar, OAr', NH ₂ , NHA, NA ₂ , NO ₂ , CN, shark, NHCOA, NHCOAr ', NHSO ₂ A, NHSO ₂ Ar', COOH, COOA, CONH ₂ , CONHA, CONA ₂ , CONHAr ', COA, COAr', S (O ) Λ S (O), / Ar ', SO ₂ NH ₂ , S0 ₂ NHA or SO ₂ NA ₂ substituted phenyl, naphthyl or biphenyl or a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N-, O - and / or S atoms, bound via N or C, which is unsubstituted or mono- or triple by R ⁸ , A, Ar ', OH, OA, O (C (R ³ ) ₂ ) _n -Ar, OAr ', NH ₂ , NHA, NA ₂ , NO ₂ , CN, Hai, NHCOA, NHCOAr', NHSO ₂ A, NHSO ₂ Ar ', COOH, COOA, CONH ₂ , CONHA, CONA ₂ , CONHAr', COA, COAr ' , S (O) _n A, SfO), / ^ SO ₂ NH ₂ , SO ₂ NHA or

SO ₂ NA ₂ or carbonyl oxygen can be substituted, where A, Ar 'and Hai have one of the meanings given above and R ³ and R ^{8 have} one of the meanings given below. The meaning of the mono- or dinuclear saturated, unsaturated or aromatic heterocycle is in accordance with the meaning of Het given above.

Unsubstituted phenyl, 2-naphthyl, 3-naphthyl, 3- or 4-biphenylyl, with Cl, propyl, isopropyl, methoxy or is particularly preferred for R ² C (= NH) -NH ₂ substituted phenyl, 1-naphthyl, 2-naphthyl, 3-naphthyl or 4-biphenylyl.

Very particularly preferably R ² is unsubstituted phenyl, 4-propylphenyl, 1-naphthyl, 2-naphthyl or 4-biphenylyl, 2'-sulfamoyl-biphenyl-4-yl, 2'-tert.Butylsulfamoyl-biphenyl-4-yl, 3-amidinophenyl, 4-

Amidinophenyl, 4-isopropylphenyl, 3,5-dimethoxyphenyl, 5-chloro-1-naphthyl, 5-chloro-2-naphthyl, 6-chloro-2-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2- naphthyl or 7-amidino-2-naphthyl.

R ³ is preferably H or A, where A has one of the meanings given above. More preferably R ³ is H.

R ⁴ , R ⁵ , R ⁶ or R ⁷ are each independently H, A, (C (R ³ ) ₂ ) _n -Ar, (C (R ³ ) ₂ ) _n -Het, (C (R ³ ) ₂ ) _n -COOH or (C (R ³ ) ₂ ) _n -COOA, where A, Ar, Het and R ^{3 have} one of the meanings given above and n can mean 0, 1 or 2. H, methyl, benzyl, CH ₂ -COOMe or CH ₂ - COOH is particularly preferred for R ⁴ , R ⁵ , R ⁶ or R ⁷ each independently of one another.

R ⁸ is preferably unsubstituted or simply substituted by COA, CO- [C (R ³ ) ₂ ] _π -Ar, COOA, OH or by a conventional amino protecting group C (= NH) -NH ₂ , unsubstituted NH-C (= NH ) -NH ₂ , CON = C (NH ₂ ) ₂ ,

where A, Ar and R ^{3 have} one of the meanings given above and n can mean 0, 1 or 2.

Unsubstituted C (= NH) -NH ₂ is particularly preferred for R ⁸ ,

W is preferably -CO- or C (R ³ ) ₂ , where R ^{3 has} one of the meanings given above, particularly preferably for W is -CO- or CH ₂ .

X is preferably - (C (R ³ ) ₂ ) _n , -SO ₂ , -CO-, -COO- or -CONR ⁴ -, where R ³ and R ^{4 have} one of the meanings given above and n is 0, 1 or 2 can mean. X is particularly preferably -SO ₂ -, -CO- or CH ₂ .

The compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms. Formula I encompasses all of these forms.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas la to le, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which

in la W represents CH ₂ ;

in Ib W means CO;

in Ic X is SO ₂ ;

in Id X means CO; in le X CH means.

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.

Compounds of formula I can preferably be obtained by liberating compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, in particular those which have a instead of an HN group R'-N group, in which R 'is an amino protecting group and / or those which carry a hydroxyl protecting group instead of the H atom of a hydroxyl group, for example those which correspond to the formula I, but instead of a group -COOH a group -COOR "wear where R" is a hydroxy protecting group. Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.

The introduction of the oxadiazole group succeeds e.g. by reacting the cyan compounds with hydroxylamine and reaction with phosgene,

Dialkyl carbonate, chloroformate, N, N'-carbonyldiimidazole or acetic anhydride.

The release of the amidino group from its oxadiazole derivative can e.g. by treatment with hydrogen in the presence of a catalyst (e.g. Raney nickel). Suitable solvents are those specified below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof. The hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar.

Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.

The term "amino protecting group" is well known and refers to groups which are suitable for replacing an amino group before chemical ones

Protect (block) reactions that are easily removed after the desired chemical reaction has been performed elsewhere in the molecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protecting groups after the desired reaction (or reaction sequence) are removed, their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyi group" is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or suifonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenyiacetyl; Aroyl such as benzoyl or toluyl;

Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, Fmoc; Arylsifonyl such as Mtr. Preferred amino protecting groups are BOC, furthermore CBZ, Fmoc, benzyl and acetyl.

The term "hydroxyl protecting group" is also generally known and refers to groups which are suitable for protecting a hydroxyl group from chemical reactions, but which are easily removable after the desired chemical reaction at other points in the

Molecule has been carried out. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups. The nature and size of the hydroxyl protective groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred. Examples of hydroxyl protective groups include benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred. Depending on the protective group used, the compounds of formula I can be liberated from their functional derivatives, for example with strong acids, expediently with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as Trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 ° C, preferably between 15 and 30 ° C (room temperature).

The groups BOC and O-tert-butyl can e.g. preferably with TFA in

Dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 ° C, the Fmoc group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 ° C.

Hydrogenolytically removable protective groups (for example CBZ or benzyl) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, advantageously on a support such as carbon). Suitable solvents are those mentioned above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is in usually carried out at temperatures between about 0 and 100 ° C and pressures between about 1 and 200bar, preferably at 20-30 ° C and 1-10 bar. Hydrogenolysis of the CBZ group works well, for example, on 5 to 10% Pd / C in methanol or ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 ° C.

Compounds of the formula I,

where R ⁸ means

and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , W and X have the meanings given in Claim 1 can preferably be obtained by reacting compounds of the formula II with compounds of the formula III . 5

In the compounds of formula III, L preferably denotes Cl, Br, I or a reactively modified OH group such as e.g. activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyioxy) or arylsulfonyloxy with 6-10 C atoms (preferably Q phenyl- or p-tolylsulfonyloxy).

The reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal, preferably potassium, sodium, Calcium or cesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline is also preferred. The use of 4-dimethylaminopyridine on polystyrene is particularly preferred. Depending on the Q and the conditions used, the response time is between a few minutes and several Days, the reaction temperature between about 0 ° and 150 ° C, usually between 20 ° and 100 ° C, preferably between 20 ° and 40 °.

Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as

Trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or

Ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, N-methyl-pyrrolidone (NMP), dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

Compounds of the formula I in which R ^{8 is} an amidino group and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , W and X are those specified in claim 1

Meanings can preferably be obtained by liberating them from their oxadiazole derivatives by treatment with a solvolysing or hydrogenolysing agent as previously described.

Compounds of the formula I in which R ^{8 is} -C (= NH) -NH ₂ can furthermore be obtained from the corresponding cyano compound. The conversion of a cyano group into an amidino group takes place by reaction with, for example: hydroxylamine and subsequent reduction of the N- Hydroxyamidine with hydrogen in the presence of a catalyst such as Pd / C.

To produce an amidine of the formula I (R ¹ = -C (= NH) -NH ₂ ), ammonia can also be added to a nitrile of the formula I (R ¹ = CN). The addition is preferably carried out in several stages by using known per se

Way a) converts the nitrile with H ₂ S into a thioamide with a

Alkylating agent, for example CH ₃ I, is converted into the corresponding S-alkyl imidothioester, which in turn reacts with NH ₃ to give the amidine, b) converts the nitrile into the corresponding imido ester with an alcohol, for example ethanol in the presence of HCl, and this with ammonia treated, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and then hydrolyzing the product.

The starting compounds of the formula II and III are generally known.

If they are new, they can be manufactured according to methods known per se.

Starting compounds of the formula II with R ⁴ , R ⁵ = H are prepared according to the following synthesis scheme:

The parameters R ¹ , R ³ , R ⁷ , R ⁶ , W and L used in the synthesis scheme have the meanings given in Claims 1 and 3. LDA means lithium diisopropylamide.

It is also possible to convert a compound of the formula I into another compound of the formula I by one or more radicals W, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and / or R ⁸ into one or more radicals W, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and / or R ⁸ , for example by acylating an amino group or nitro groups (for example reduced to amino groups by hydrogenation on Raney nickel or Pd carbon in an inert solvent such as methanol or ethanol).

For the esterification, an acid of the formula I (R ⁴ , R ⁵ , R ⁶ or R ⁷ = COOH) can be treated with an excess of an alcohol, advantageously in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 0 ° and 100 ° C. , preferably between 20 ° and 50 ° C.

Conversely, an ester of the formula I (R ⁴ , R ⁵ , R ⁶ or R ⁷ = COOA) can be converted into the corresponding acid of the formula I, advantageously by solvoysis by one of the methods given above, for example using NaOH or KOH in water. Dioxane at temperatures between 0 ° and 100 ° C, preferably between 10 ° and 30 ° C. Furthermore, free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a

Base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aiiphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, For example formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or toluenesulfonic acid, mononethane sulphonic acid, ponic acid and disulfonic acids or lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I. On the other hand, compounds of the formula I with bases (for example sodium or potassium hydroxide or carbonate) can be added to the corresponding metal, in particular alkali metal or alkaline earth metal or be converted into the corresponding ammonium salts.

Compounds of the formula I according to the invention can be chiral due to their molecular structure and can accordingly occur in various enantiomeric forms. They can therefore be in racemic or optically active form.

Since the pharmaceutical activity of the racemates or the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical, biochemical or physical measures known to the person skilled in the art, or can already be used as such in the synthesis.

Thus, diastereomers can be formed from the racemate by reaction with an optically active release agent. Suitable release agents for basic compounds of the formula I are, for example optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,

Mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonylproiin) or the various optically active camphorsulfonic acids. Chromatographic separation of enantiomers with the aid of an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers fixed on silica gel) is also advantageous. Suitable solvents are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example in a ratio of 82: 15: 3. The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts or solvates, which are prepared in particular by a non-chemical route. The compounds of the formula I can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.

These preparations can be used as medicinal products in human or

Veterinary medicine can be used. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate,

Gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, and solutions, preferably oily or aqueous solutions, for parenteral use

Suspensions, emulsions or implants, for topical application of ointments, creams or powders. The new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables. The specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives,

Stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active ingredients, for example one or more vitamins. The compounds of formula I and their physiologically acceptable salts can be used in the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.

The substances according to the invention are generally administered in the dosage preferably between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg

Body weight. However, the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, gender, on the diet, on the time and route of administration, on which

Elimination rate, drug combination and severity of the disease to which the therapy applies. Oral application is preferred.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried organic phase over sodium sulfate, evaporated and purified by chromatography

Silica gel and / or by crystallization. Mass spectrometry (MS): El (electron impact ionization) M ⁺

FAB (Fast Atom Bombardment) (M + H) ⁺ Example 1: a) Preparation of the starting compound ("A"): 1- [4- (5-methyl-

[1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one

To a solution of 88.8 g (510 mmol) of 3- (4-methylphenyl) -5-methyl-

[1, 2,4] oxadiazole (Schubart et al. Chem. Ber. 1889, 22, 2433) 90.73 g (510 mmol) of N-bromosuccinimide are added and the resulting suspension is heated to boiling under the light of a UV lamp for 1 hour . The mixture is allowed to cool, filtered and the filtrate is evaporated. The evaporation residue is recrystallized from tert-butyl methyl ether. 3- (4-Bromomethyl-phenyl) -5-methyl- [1, 2,4] oxadiazole is obtained as a colorless solid; M. 113-114 °.

Then a solution of 1.25 g (6.24 mmol) of 4- (tert-butoxycarbonyl) -piperazin-2-one (John M. Kane, Albert A. Carr, Tetrahedron Lett. 1980, 21, 3019-3020) and 1, 423 g of 3- (4-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazole in 25 ml of acetonitrile, 2.12 g (6.5 mmol) of CsCO _{3 was} added and the suspension was stirred for 4 days at room temperature. The reaction mixture is filtered, the filtrate is evaporated and the residue is stirred with ethyl acetate / petroleum ether. 4- [4- (5-Methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] -3-oxo-piperazin-1-carboxylic acid tert-butyl ester is obtained; El-MS 372.

To remove the protective group, a solution of 1.70 (4.57 mmol) 4- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] -3-oxo-piperazin- 1-carboxylic acid tert-butyl ester in 15 ml of methanol with 5 ml of 4 N HCl in dioxane and stirred for 18 hours at room temperature. The

The reaction mixture is evaporated, taken up in dichloromethane, mixed with basic ion exchanger and stirred for 30 minutes. After filtration and evaporation, 1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one ("A)" is obtained; El-MS 272. b) Reaction of "A" with 6-chloro-naphthalene-2-sulfonylchloride

A solution of 100 mg (0.367 mmol) 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2-one ("A") and 106 mg ( 0.406 mmol) 6-chloro-naphthalene-2-sulfonyl chloride in 5 ml dichloromethane is mixed with 300 mg 4-dimethylaminopyridine on polystyrene and stirred for 48 hours at room temperature. The reaction mixture is filtered and the filtrate is evaporated. 4- (6-chloro-naphthalene-2-sulfonyl) -1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one is obtained; FAB-MS 497.

Analogously, by reacting compound "A"

with naphthalene-2-sulfonyl chloride

4- (naphthalene-2-sulfonyl) -1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with biphenyl-4-carbonyl chloride

4- (biphenyl-4-carbonyl) -1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with naphthalene-2-carbonyl chloride

4- (naphthalene-2-carbonyl) -1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 2-bromomethyl-naphthalene

1- [4- (5-Methyl- [1, 2,4] oxadiazol-3-yl) benzyl] -4-naphthalin-2-ylmethylpiperazin-2-one;

with 6-methoxy-naphthalene-2-sulfonyl chloride 4- (6-methoxy-naphthalen-2-sulfonyl) -1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 7-methoxy-naphthalene-2-sulfonyl chloride

4- (7-methoxy-naphthalene-2-sulfonyl) -1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 3- (4-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazole 1, 4-bis- [4- (5-methyi- [1, 2,4] oxadiazol-3-yl) -benzyl] -piperazin-2-one;

with 3- (3-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazol 4- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] - 1 - [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 3- (7-bromomethyl-naphthalene) -5-methyl- [1, 2,4] oxadiazol 1 - [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] - 4- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] -piperazin-2-one.

Example 2: A solution of 107 mg (0.215 mmol) of 4- (6-chloro-naphthalene-2-sulfonyl) -1-

[4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one in 5 ml methanol is mixed with 100 mg water-wet Raney nickel and 30 mg acetic acid and 18 hours hydrogenated at room temperature and normal pressure. The reaction mixture is filtered and the residue is evaporated. 4- [4- (6-chloro-naphthalene-2-sulfonyi) -2-oxopiperazin-1-ylmethyl] benzamidine acetate is obtained; FAB-MS 457.

The following piperazinone derivatives are obtained analogously from the compounds obtained in Example 1 by hydrogenation 4- [4- (naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 423;

4- [4- (biphenyl-4-carbonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 413;

4- [4- (naphthalene-2-carbonyl) -2-oxopiperazin-1-ylmethyi] benzamidine acetate; FAB-MS 387;

4- (4-Naphthalin-2-ylmethyl-2-oxopiperazin-1 -ylmethyl) benzamidine

Diacetate; FAB-MS 373;

4- [4- (6-methoxy-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 453;

4- [4- (7-methoxy-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 453;

4- [4- (4-Amidino-benzyl) -2-oxopiperazin-1-ylmethyl] benzamidine triacetate; FAB-MS 365;

4- [4- (3-Amidino-benzyl) -2-oxopiperazin-1-ylmethyl] benzamidine triacetate; FAB-MS 365;

7- [4- (4-Carbamimidoyl-benzyl) -3-oxopiperazin-1-ylmethyl] -naphthaiine-2-carboxamidine triacetate; FAB-MS 415.

Example 3:

A solution of 100 mg (0.367 mmol) of 1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one ("B") [obtainable by reaction from 3- (3- Methylphenyl) -5-methyl- [1, 2,4] oxadiazole with NBS, coupling of the reaction product with 4- (tert-butoxycarbonyl) piperazin-2-one and removal of the protective group with HCl / dioxane analogously to Example 1a)] and 106 mg (0.406 mmol) of 6-chloro-naphthalene-2-sulfonyl chloride in 5 ml of dichloromethane are mixed with 300 mg of 4-dimethylaminopyridine on polystyrene and stirred for 48 hours at room temperature. The reaction mixture is filtered and the filtrate is evaporated. 4- (6- Chlomaphthalin-2-suifonyl) -1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] - piperazin-2-one is obtained.

Analogously, by reacting compound "B"

with naphthalene-2-sulfonyl chloride

4- (naphthaiin-2-sulfonyl) -1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with biphenyl-4-carbonyl chloride

4- (biphenyl-4-carbonyl) -1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with naphthalene-2-carbonyl chloride

4- (naphthalene-2-carbonyl) -1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 4-isopropyl-benzenesulfonyl chloride

4- (4-isopropyl-benzenesulfonyl) -1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 6-methoxy-naphthalene-2-sulfonyl chloride 4- (6-methoxy-naphthalene-2-sulfonyl) -1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 7-methoxy-naphthalene-2-sulfonyl chloride 4- (7-methoxy-naphthalene-2-sulfonyl) -1 - [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) - benzyl] -piperazin-2-one;

with 3- (4-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazol 4- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] - 1 - [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 3- (3-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazole 1, 4-bis- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] -piperazin-2-one;

with 3- (7-bromomethyl-naphthalene) -5-methyl- [1, 2,4] oxadiazol 1 - [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] - 4- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] -piperazin-2-one.

Example 4: A solution of 107 mg (0.215 mmol) of 4- (6-chloro-naphthalene-2-sulfonyl) -1-

[3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one in 5 ml methanol is mixed with 100 mg water-wet Raney nickel and 30 mg acetic acid and 18 hours hydrogenated at room temperature and normal pressure. The reaction mixture is filtered and the residue is evaporated. This gives 3- [4- (6-chloro-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 457.

The following piperazinone derivatives are obtained analogously from the compounds obtained in Example 3 by hydrogenation 3- [4- (naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 423;

3- [4- (biphenyl-4-carbonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 413;

3- [4- (4-isopropyl-benzenesulfonyl) -2-oxopiperazin-1-ylmethyl] benzamide acetate; FAB-MS 415;

3- [4- (6-methoxynaphthaiine-2-suifonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 453;

3- [4- (7-methoxynaphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 453;

3- [4- (4-Amidino-benzyl) -2-oxopiperazin-1-ylmethyl] benzamidine in triacetate; FAB-MS 365;

3- [4- (3-Amidino-benzyl) -2-oxopiperazin-1-ylmethyi] benzamidine triacetate: FAB-MS 365;

7- [4- (3-Carbamimidoyl-benzyl) -3-oxopiperazin-1-ylmethyl] -naphthalene-2-carboxamidine triacetate; FAB-MS 365.

Example 5:

Analogously to Example 1, 1- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] -piperazin-2-one ("C") [obtainable by reaction of 5-methyl-3- (7-methyl-naphthalin-2-yl) - [1, 2,4] oxadiazole with NBS, coupling of the reaction product with 4- (tert-butoxycarbonyl) piperazin-2-one and cleavage the protecting group with HCI / dioxane analogously to Example 1a)] with 6- Chloro-naphthalene-2-sulfonyl chloride implemented. 4- (6-Chloro-naphthalene-2-sulfonyl) -1- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] piperazin-2 is obtained -on.

Analogously, by reacting compound "C"

with naphthalene-2-sulfonyl chloride

4- (naphthalene-2-sulfonyl) -1- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] piperazin-2-one;

with biphenyl-4-carbonyl chloride

4- (biphenyl-4-carbonyl) -1- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] piperazin-2-one;

with naphthalene-2-carbonyl chloride

4- (naphthalene-2-carbonyl) -1- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] piperazin-2-one;

with 4-isopropyl-benzenesulfonyl chloride 4- (4-isopropyl-benzoisuifonyl) -1 - [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) - naphthalen-2-ylmethyl] piperazin-2 -on;

with 1-bromomethyl-3,5-dimethoxybenzene

4- (3,5-dimethoxybenzyl) -1- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) -naphthalen-2-yimethyl] piperazin-2-one;

with 6-methoxy-naphthalene-sulfonyl chloride

4- (6-methoxy-naphthalenesulfonyl) -1- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyi] piperazin-2-one; with 7-methoxy-naphthalene-sulfonyl chloride

4- (7-methoxy-naphthalenesulfonyl) -1- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) naphthalen-2-yimethyl] piperazin-2-one;

with 2-bromomethylnaphthalene

4- (naphthalen-2-ylmethyl) -1- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] piperazin-2-one;

with 4-bromomethyl-biphenyl 4- (biphenyl-4-ylmethyl) -1 - [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalin-2-ylmethyl] -piperazin- 2-one;

with 3- (4-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazol 4- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] - 1 - [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] piperazin-2-one;

with 3- (3-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazol 4- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] - 1 - [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalin-2-ylmethyi] piperazin-2-one.

Example 6:

Analogously to Example 2, the following piperazinone derivatives are obtained from the compounds obtained in Example 5 by hydrogenation

7- [4- (6-chloro-naphthalene-2-sulfonyl) -2-oxo-piperazin-1-ylmethyl] -naphthalene

2-carboxamidine acetate;

7- [4- (naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] naphthalene-2-carboxamidine acetate; 7- [4- (Biphenyl-4-carbonyl) -2-oxopiperazin-1-yimethyl] naphthalene-2-carboxamidine acetate;

7- [4- (naphthalene-2-carbonyl) -2-oxopiperazin-1-ylmethyl] naphthalene-2-carboxamidine acetate;

7- [4- (4-isopropylbenzoisulfonyl) -2-oxopiperazin-1-ylmethyl] naphthalene-2-carboxamidine acetate;

7- [4- (3,5-dimethoxybenzyl) -2-oxopiperazin-1-ylmethyl] naphthalene-2-carboxamidine acetate;

7- [4- (6-methoxy-naphthalene-2-sulfonyl) -2-oxo-piperazin-1-ylmethyl] - naphthalene-2-carboxamidine acetate;

7- [4- (7-methoxy-naphthalene-2-sulfonyl) -2-oxo-piperazin-1-ylmethyl] - naphthaiine-2-carboxamidine diacetate; FAB-MS 423;

7- [4- (naphthalin-2-ylmethyl) -2-oxopiperazin-1-ylmethyl] naphthalene-2-carboxamidine acetate;

7- [4- (biphenyl-4-ylmethyl) -2-oxopiperazin-1-ylmethyl] naphthalene-2-carboxamidine acetate;

7- [4- (4-Carbamimidoyl-benzyl) -2-oxopiperazin-1-ylmethyl] naphthalene-2-carboxamidine acetate;

7- [4- (3-Carbamimidoyl-benzyl) -2-oxopiperazin-1-ylmethyl] -naphthalene-2-carboxamidine acetate. Example 7:

Analogously to Example 1, 1-benzyl-piperazin-2-one ("D") [obtainable by coupling benzyl bromide with 4- (tert-butoxycarbonyl) -piperazin-2-one and splitting off the protective group with HCl / dioxane analogously to Example 1a)] with 3- (4-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazole. 1-Benzyl-4- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one is obtained; FAB-MS 363.

Analogously, by reacting compound "D"

with 3- (3-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazol 1-benzyl-4- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] -piperazin-2-one;

with 3- (7-bromomethyl-naphthalene) -5-methyl- [1, 2,4] oxadiazol 1-benzyl-4- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalin-2-ylmethyl] - piperazin-2-one.

Example 8:

Analogously to Example 2, the following piperazinone derivatives are obtained from the compounds obtained in Example 7 by hydrogenation

4- (4-benzyl-3-oxo-piperazin-1-ylmethyl) benzamidine diacetate; FAB-MS 323;

3- (4-benzyl-3-oxopiperazin-1-ylmethyl) benzamidine diacetate; FAB-MS 323;

7- (4-Benzyl-3-oxopiperazin-1-ylmethyl) naphthalene-2-carboxamidine diacetate; FAB-MS 373. Example 9:

Analogously to Example 1, 1- (3,5-dimethoxybenzyl) piperazin-2-one [obtainable by coupling 3,5-dimethoxybenzyl bromide with 4- (tert-butoxycarbonyl) piperazin-2-one and splitting off the Protecting group with HCl / dioxane analogously to Example 1a)] with 3- (7-bromomethyl-naphthalene) -5-methyl- [1, 2,4] oxadiazole ("E"). 1- (3,5-Dimethoxybenzyl) -4- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] piperazin-2-one is obtained .

Analogously, reaction of 1-naphthalin-2-ylmethyl-piperazin-2-one [obtainable by coupling 2-bromomethyl-naphthalene with 4- (tert-butoxycarbonyl) -piperazin-2-one and removal of the protective group with HCl / Dioxane analogous to Example 1a)] with "E" 1- (naphthalen-2-ylmethyl) -4- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthaiin- 2-ylmethyl ] -piperazin-2-one.

Analogously, reaction of 1-biphenyl-4-ylmethyl-piperazin-2-one [obtainable by coupling 4-bromomethyl-biphenyl with 4- (tert-butoxycarbonyl) piperazin-2-one and splitting off the protective group with HCl / Dioxane analogous to Example 1a)] with "E"

1- (Biphenyl-4-ylmethyl) -4- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] piperazin-2-one.

Example 10: Analogously to Example 2, the following piperazinone derivatives are obtained from the compounds obtained in Example 9 by hydrogenation

7- (4- (3,5-Dimethoxybenzyl) -3-oxopiperazin-1-ylmethyl) naphthalene-2-carboxamidine acetate; 7- (4-Naphthalin-2-ylmethyl-3-oxopiperazin-1-ylmethyl) naphthalene-2-carboxamidine acetate;

7- (4-Biphenyl-4-ylmethyl-3-oxopiperazin-1-ylmethyl) naphthalene-2-carboxamidine acetate.

Example 11:

Analogously to Example 1, 1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2,6-dione ("F") [obtainable by reacting 3 - (4-methylphenyl) -5-methyl- [1, 2,4] oxadiazole with NBS, coupling of the

Reaction product with 3,5-dioxopiperazine-1-carboxylic acid tert-butyl ester and removal of the protective group with HCl / dioxane analogously to Example 1a)] with 6-chloro-naphthalene-2-sulfonyl chloride. 4- (6-Chloro-naphthalene-2-sulfonyl) -1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2,6-dione is obtained .

Analogously, by implementing the compound "F"

with naphthalene-2-sulfonyl chloride 4- (naphthalene-2-sulfonyl) -1 - [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] - piperazin-2,6-dione ;

with 7-methoxy-naphthalene-2-sulfonyl chloride

4- (7-methoxy-naphthalene-2-sulfonyl) -1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2,6-dione.

Example 12:

Analogously to Example 2, the following piperazinone derivatives are obtained from the compounds obtained in Example 11 by hydrogenation 4- [4- (6-chloro-naphthalene-2-sulfonyl) -2,6-dioxopiperazin-1-yimethyl] benzamidine acetate;

4- [4- (naphthalene-2-sulfonyi) -2,6-dioxopiperazin-1-ylmethyl] benzamidine acetate;

4- [4- (7-methoxy-naphthalene-2-sulfonyl) -2,6-dioxopiperazin-1-ylmethyl] benzamidine acetate.

Example 13:

Analogously to Example 1, 1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2,6-dione ("G") [obtainable by reacting 3 - (3-Methylphenyl) -5-methyl- [1, 2,4] oxadiazole with NBS, coupling of the reaction product with 3, 5-dioxo-piperazin-1-carboxylic acid tert-butyl ester and removal of the protective group with HCl / dioxane analogously to Example 1a)] with 6-chloro-naphthalene-2-sulfonyl chloride. 4- (6-Chloro-naphthalene-2-sulfonyl) -1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2,6-dione is obtained .

Analogously, by reacting compound "G"

with naphthalene-2-sulfonyl chloride

4- (naphthaiin-2-sulfonyl) -1- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2,6-dione;

with 7-methoxy-naphthalene-2-sulfonyl chloride

4- (7-methoxy-naphthalene-2-sulfonyl) -1- [3- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2,6-dione. Example 14:

Analogously to Example 2, the following piperazinone derivatives are obtained by hydrogenation from the compounds obtained in Example 13

3- [4- (6-chloro-naphthalene-2-sulfonyl) -2,6-dioxopiperazin-1-ylmethyl] benzamidine acetate;

3- [4- (naphthalene-2-sulfonyl) -2,6-dioxopiperazin-1-ylmethyl] benzamidine acetate;

3- [4- (7-methoxy-naphthalene-2-sulfonyl) -2,6-dioxopiperazin-1-ylmethyl] benzamidine acetate.

Example 15: To a solution of 1.25 g (6.24 mmol) of 4- (tert-butoxycarbonyi) -piperazin-2-one in 25 ml of THF, 2.2 eq. LDA and then 0.95 g (6.24 mmol) of methyl 2-bromoacetate and the mixture was stirred until conversion was complete. After thawing and customary work-up, tert-butyl 2-methoxycarbonylmethyl-3-oxopiperazine-1-carboxylate is obtained.

To a solution of 2-methoxycarbonylmethyl-3-oxo-piperazin-1-carboxylic acid tert-butyl ester and 1,423 g of 3- (4-bromomethyl-phenyl) -5-methyl- [1, 2,4] oxadiazole in 25 ml 2.12 g (6.5 mmol) of CsCO _{3 are} added to acetonitrile and the suspension is stirred for 4 days at room temperature. The reaction mixture is filtered, evaporated and the residue with

Stirred ethyl acetate / petroleum ether. 2-Methoxycarbonylmethyl-4- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] -3-oxo-piperazin-1-carboxylic acid tert-butyl ester is obtained. Analogously to Example 1, the protective group is split off and (4- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] -3-oxopiperazin-2-yl} is obtained. methyl acetate. This compound is reacted with 6-chloro-naphthalene-2-sulfonyl chloride analogously to Example 1 and the piperazinone derivative is obtained

{1- (6-chloro-naphthalene-2-sulfonyl) -4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -3-oxopiperazin-2- yl} methyl acetate.

Example 16:

Analogously to Example 2, the compound obtained in Example 15 is obtained by hydrogenation

[4- (4-Carbamimidoyl-benzyl) -1- (6-chloro-naphthalene-2-sulfonyl) -3-oxopiperazin-2-yl] -acetic acid methyl ester.

Example 17: A solution of 0.367 mmol {1- (6-chloro-naphthalene-2-sulfonyl) -4- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] - 3-oxo-piperazin-2-yl} - methyl acetate in 10 ml of methanol is mixed with 0.367 mmol of NaOH in 5 ml of methanol and stirred at room temperature until conversion is complete. After cooling and usual work-up, {1 - (6-chloro-naphthalene-2-sulfonyl) -4- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] -3 is obtained -oxo-piperazin-2-yl} acetic acid.

Example 18:

Analogously to Example 2, hydrogenation is obtained from the compound obtained in Example 17

[4- (4-Carbamimidoyl-benzyl) -1- (6-chloro-naphthalene-2-sulfonyl) -3-oxopiperazin-2-yl] acetic acid. Example 19:

Analogously to Example 15, 4- (tert-butoxycarbonyl) piperazin-2-one is reacted with benzyl bromide and then with 3- (4-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazole, the protective group split off and the reaction product reacted with 6-chloro-naphthalene-2-suifonyl chloride. 3-Benzyl-4- (6-chloro-naphthalene-2-sulfonyl) -1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2 is obtained -on.

Example 20: Analogously to Example 2, hydrogenation is obtained from the compound obtained in Example 19

4- [3-benzyl-4- (6-chloro-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate.

Example 21:

Analogously to Example 15, 4- (tert-butoxycarbonyl) piperazin-2-one is reacted with 3,5-dimethoxybenzylbromide and then with 3- (4-bromomethylphenyl) -5-methyl- [1, 2.4 ] reacted oxadiazole, the protective group split off and the reaction product reacted with 6-chloro-naphthalene-2-sulfonyl chloride. 3- (3,5-Dimethoxy-benzyl) -4- (6-chloro-naphthalene-2-sulfonyl) -1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl ) -benzyl] -piperazin-2-one.

Example 22: Analogously to Example 2, hydrogenation is obtained from the compound obtained in Example 21

4- [3- (3,5-Dimethoxy-benzyl) -4- (6-chloro-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethylj-benzamidine acetate. Example 23:

Analogously to Example 15, 4- (tert-butoxycarbonyl) piperazin-2-one is reacted with methyl iodide and then with 3- (4-bromomethylphenyl) -5-methyl- [1, 2,4] oxadiazole, the protective group split off and the reaction product reacted with 6-chloro-naphthalene-2-sulfonyl chloride. 3-Methyl-4- (6-chloro-naphthalene-2-sulfonyl) -1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzyl] -piperazin-2 is obtained -on.

Example 24: Analogously to Example 2, hydrogenation is obtained from the compound obtained in Example 23

4- [3-Methyl-4- (6-chloro-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate.

Example 25:

Analogously to Example 3, reaction of compound "B" gives

with 5-chloro-naphthalene-2-sulfonyl chloride 4- (5-chloro-naphthalene-2-sulfonyl) -1 - [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) - benzyi] -piperazin-2-one;

with biphenyl-4-sulfonyl chloride

4- (biphenyl-4-sulfonyl) -1- [3- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with naphthalene-1-sulfonyl chloride

4- (naphthalene-1-sulfonyl) -1 - [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one; with 5-chloro-naphthalene-1-sulfonyl chloride

4- (5-chloro-naphthalen-1-sulfonyl) -1 - [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 4-bromomethyl-biphenyl

4- (Biphenyl-4-ylmethyi) -1- [3- (5-methyi- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one.

Example 26: Analogously to Example 4, the following piperazinone derivatives are obtained from the compounds obtained in Example 25 by hydrogenation

3- [4- (5-chloro-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 457;

3- [4- (biphenyl-4-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 449;

3- [4- (naphthalene-1-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 423;

3- [4- (5-chloro-naphthalene-1-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 457;

3- [4- (biphenyl-4-ylmethyl) -2-oxopiperazin-1-yimethyl] benzamidine acetate; FAB-MS 399.

Example 27:

Analogously to Example 1, reaction of compound "A" gives with 5-chloro-naphthalene-2-sulfonyl chloride

4- (5-chloro-naphthalene-2-sulfonyl) -1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with naphthaiine-1-sulfonyl chloride

4- (naphthalene-1 sulfonyl) -1 - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with 4-bromomethyl-biphenyl 4- (biphenyl-4-ylmethyl) -1 - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2-one;

with biphenyl-4-sulfonyl chloride

4- (Biphenyl-4-sulfonyl) -1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazin-2-one.

Example 28:

Analogously to Example 2, the following piperazinone derivatives are obtained from the compounds obtained in Example 27 by hydrogenation

4- [4- (5-chloro-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 457;

4- [4- (naphthalene-1-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 423;

4- [4- (biphenyl-4-ylmethyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 399; 4- [4- (biphenyl-4-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate; FAB-MS 449.

Example 29:

Analogously to Example 5, reaction of compound "C" gives

with 4-propyl-phenyl-sulfonyl chloride

4- (4-propylphenylsulfonyl) -1- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) naphthalen-2-ylmethyl] piperazin-2-one;

with biphenyl-4-sulfonyl chloride

4- (Biphenyl-4-sulfonyl) -1- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] piperazin-2-one.

Example 30:

Analogously to Example 6, the following piperazinone derivatives are obtained from the compounds obtained in Example 29 by hydrogenation

7- [4- (4-propylphenylsulfonyl) -2-oxopiperazin-1-ylmethyl] naphthalene-2-carboxamidine acetate; FAB-MS 465;

7- [4- (biphenyl-4-sulfonyl) -2-oxopiperazin-1-ylmethyl] naphthalene-2-carboxamidine acetate; FAB-MS 499.

Example 31:

Analogously to Example 1, reaction of compound "A" gives

with 4'-bromomethyl-biphenyl-2-sulfonic acid tert-butylamide 4- (2'-tert-Butylsuifamoyl-biphenyl-4-ylmethyl) -1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl] piperazin-2-one ;

with 2'-tert-butylsulfamoyl-biphenyl-4-carboxylic acid 4- (2'-tert-butylsulfamoyl-biphenyl-4-carbonyl) -1- [4- (5-methyl-

[1, 2,4] oxadiazoi-3-yl) benzyl] piperazin-2-one;

with 2'-tert-butylsulfamoyl-biphenyl-3-carboxylic acid 4- (2'-tert-butylsulfamoyl-biphenyl-3-carbonyl) -1- [4- (5-methyl- [1, 2,4] oxadiazole -3-yl) benzyl] piperazin-2-one.

Example 32:

Analogously to Example 2, the following piperazinone derivatives are obtained from the compounds obtained in Example 31 by hydrogenation

4- [4- (2'-tert-Butylsulfamoyl-biphenyl-4-ylmethyl) -2-oxopiperazin-1-ylmethyl] benzamidine diacetate; FAB-MS 534;

4- [4- (2'-tert-butylsulfamoyl-biphenyl-4-carbonyl) -2-oxopiperazin-1-ylmethyl] benzamidine diacetate;

4- [4- (2'-tert-Butylsulfamoyl-biphenyl-3-carbonyl) -2-oxopiperazin-1-ylmethyl] benzamidine diacetate.

Example 33:

1.31 mmol of anisole and 7 ml of trifluoroacetic acid are added to 0.260 mmol of 4- [4- (2'-tert.-butylsulfamoyl-biphenyl-4-ylmethyl) -2-oxopiperazin-1-ylmethyl] benzamidine diacetate and transfer Stirred at night. The trifluoroacetic acid is then distilled off and diethyl ether is added to the residue. The precipitated crystals are washed and dried. 4- [4- (2'-Sulfamoyl-biphenyl-4-ylmethyl) -2-oxopiperazin-1-ylmethyij-benzamidine bistrifluoroacetate is obtained; FAB-MS 478.

Analogously, 4- [4- (2'-tert-butylsulfamoyl-biphenyl-4-carbonyl) -2-oxopiperazin-1-ylmethyl] benzamidine in diacetate is reacted with anisole and trifluoroacetic acid. 4- [4- (2'-Sulfamoyl-biphenyl-4-carbonyl) -2-oxopiperazin-1-ylmethyl] benzamidine is obtained in trifluoroacetate; FAB-MS 492.

Analogously, 4- [4- (2'-tert-butylsulfamoyl-biphenyl-3-carbonyl) -2-oxopiperazin-1-ylmethyl] -benzamidine is reacted with anisole and trifluoroacetic acid. 4- [4- (2'-Suifamoyl-biphenyl-3-carbonyl) -2-oxopiperazin-1-ylmethyl] -benzamidine trifluoroacetate is obtained; FAB-MS 492.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient. Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ -2 H ₂ O, 28.48 g of Na ₂ HPO ₄ -12 H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. The pH is adjusted to 6.8 and the solution is made up

1 I on and sterilized by radiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient. Example H: ampoules

A solution of 1 kg of active ingredient of formula I in 60 ml of double distilled

Water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims

claims

1. Compounds of formula I.

wherein

R ¹ , R ² independently of one another A, unsubstituted or one, two or three times by R ⁸ , A, Ar ', OH,

10 OA, O (C (R ³ ) ₂ ) _n -Ar, OAr ', NH ₂ , NHA, NA ₂ , NO ₂ , CN, Hai, NHCOA, NHCOAr', NHSO ₂ A, NHSO ₂ Ar ', COOH, COOA, CONH ₂ , CONHA, CONA ₂ , CONHAr ', COA, COAr', S (O) _n A, S (O) _n Ar ', SO ₂ NH ₂ , SO ₂ NHA or SO ₂ NA ₂ substituted phenyl, naphthyl or A ₅ biphenyl or a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, bonded via N or C, which is unsubstituted or mono- or triple by R ⁸ , A, Ar ', OH, OA, OAr', NH ₂ , NHA, NA ₂ , NO ₂ , CN, Hai, NHCOA, NHCOAr ', NHSO ₂ A, NHSO ₂ Ar', ₂₀ COOH, COOA, CONH ₂ , CONHA, CONA ₂ , CONHAr ', COA, COAr ¹ ,

S (O) Λ S (O) _n Ar'- S0 ₂ NH ₂ , SO ₂ NHA or SO ₂ NA ₂ or carbonyl oxygen can be substituted, with the proviso that the radical R ⁸ at least once in R ¹ or in R ² must be present or can occur in both residues R ¹ and R ² once 2 ₅ ,

R ³ H or A,

R ⁴ , R ⁵ ,

R ⁶ , R ⁷ each independently of one another H, A, (C (R ³ ) ₂ ) _n -Ar, (C (R ³ ) ₂ ) _n -Het, ₃₀ (C (R ³ ) ₂ ) _n -COOR ³ , R ^{8 is} unsubstituted or simply by COA, CO- [C (R ³ ) ₂ ] _n -Ar,

W -CO-, -C (R ³ ) ₂ ,

X - (C (R ³ ) ₂ ) _n - -SO ₂ , -CO-, -COO-, -CONR ⁴ -,

A alkyl with 1-20 C atoms, wherein one or two CH ₂ groups through

O or S atoms or by -CR ³ = CR ³ groups and also 1-7 H-

OAr ', NH ₂ , NHA, NA ₂ , NO ₂ , CN, Hai, NHCOA, NHCOAr', NHSO ^,

NHSO ₂ Ar ', COOH, COOA, CONH ₂ , CONHA, CONA ₂ , CONHAr',

COA, COAr ', S (O) -A or S O ^ r' substituted phenyl or

Naphthyl, Ar 'unsubstituted or one, two or three times by A, OH, OA,

0 (C (R ³ ) ₂ ) _n -Ar, NH ₂ , NHA, NA ₂ , NO ₂ , CN, shark, NHCOA, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , COA or S (O), / Λ substituted

Phenyl or naphthyl, Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, bonded via N or C, which is unsubstituted or mono-, di- or triple by shark , A, Ar ', OH, OA, O (C (R ³ ) ₂ ) _n -Ar', COOH, COOA,

CN, NO ₂ , NH ₂ , NHA, NA ₂ , NHCOA, NHCOAr 'and / or

Carbonyl oxygen can be substituted, Hai F, CI, Br or I, n 0, 1 or 2, and their pharmaceutically acceptable salts and solvates.

2. Compounds according to claim 1 a) 4- [4- (6-chloro-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyi] - benzamidine acetate;

b) 4- [4- (naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate;

c) 3- [4- (6-chloro-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate;

d) 3- [4- (4-isopropyl-benzenesulfonyl) -2-oxopiperazin-1-ylmethyl] benzamide acetate;

e) 4- [4- (7-methoxy-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] benzamidine acetate;

f) 7- [4- (4-carbamimidoyi-benzyl) -3-oxopiperazin-1-ylmethyi] -naphthalene-2-carboxamidine;

g) 7- [4- (6-chloro-naphthalene-2-sulfonyl) -2-oxopiperazin-1-ylmethyl] - naphthalene-2-carboxamidine acetate;

h) 7- [4- (3-carbamimidoyl-benzyl) -2-oxopiperazin-1-ylmethyl] -naphthalene-2-carboxamidine acetate;

i) 7- (4- (3,5-dimethoxybenzyl) -3-oxopiperazin-1-ylmethyl) naphthalene-2-carboxamidine acetate;

k) 3- [4- (6-chloro-naphthalene-2-sulfonyl) -2,6-dioxopiperazin-1-ylmethyl] benzamidine acetate;

I) 3- [4- (naphthalene-2-sulfonyl) -2,6-dioxopiperazin-1-ylmethyl] benzamidine acetate; m) [4- (4-Carbamimidoyl-benzyl) -1- (6-chloro-naphthaiine-2-sulfonyl) -3-oxopiperazin-2-yl] acetic acid.

3. A process for the preparation of compounds of formula I according to claim 1 and their salts and solvates, characterized in that

a) liberating them from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent, by i) releasing an amidino group from their oxadiazoide derivative by hydrogenolysis,

ii) a conventional amino protecting group by treatment with a solvolysing or hydrogenolysing agent

Replaces hydrogen or releases an amino group protected by a conventional protective group, or

b) for the preparation of compounds of the formula I,

where R ⁸ means

and o2

R ² , D R3 ³ , D R4 ⁴ , D R5 ^b , 0 R6 ⁶ , r R> 7 ⁷ , W and X have the meanings given in Claim 1,

a compound of formula II

wherein

R) 1 ¹ , D R3 ³ , Π R4 ⁴ , D R5 ⁵ , D R6 ⁶ , DR ⁷ and W have the meanings given in Claim 1 and

^R8 N II /> - C ^C H ^H ₃ ^{3 means} '

with a compound of formula III

R ² -XL III wherein

R ² and X have the meanings given in claim 1 and L is Cl, Br, I or a free or reactive functional group modified OH group, or

c) in a compound of the formula I one or more radicals W, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and / or R ⁸ into one or more radicals W, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and / or R ^{8 is} converted by, for example

i) converts a cyano group into an amidino group, ii) hydrolyzes an ester group to a carboxy group, iii) esterifies a carboxy group, iv) reduces a nitro group, v) acylating an amino group, vi) alkylating a sulfonylamino group or dealkylating an alkylated sulfonylamino group,

and or

d) converts a base or acid of the formula I into one of its salts or solvates.

4. Compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates as active pharmaceutical ingredients.

5. Compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates as inhibitors of the coagulation factor Xa.

6. Compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates for combating thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.

7. Pharmaceutical preparation characterized by a content of at least one compound of formula I according to claim 1 and / or one of its physiologically acceptable salts or solvates.

8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts or solvates for the manufacture of a medicament. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts or solvates in the control of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.